This project will examine the relation of oligomeric and fibrillar amyloid-p (AP) species with changes in postsynaptic dendritic spines and pre-synaptic axonal terminals within the cortical default mode network (DMN) over the clinical progression of Alzheimer's disease (AD). To gain greater insight into the structural basis of functional deficits and how they relate to amyloid pathology in these regions, we propose to quantify AB and synaptic changes in postmortem brain tissues from subjects with no cognitive impairment (NCI), mild cognitive impairment (MCI), or early AD. We will divide NCI subjects into low/no pathology (LP-NCl) and high pathology (HP-NCl) groups which are considered to be preclinical AD cases, to examine synaptic changes in the presence of AB at the earliest stages of the disease. AB analyses will target oligomeric AB in the synaptosomal compartment, and N-terminus truncated and pyroglutamate modified (NpE) AB. Spatial relation of synaptic markers with oligomeric and NpE AB deposits will be analyzed by confocal microscopy. To complete our proposed Aims, first we will quantify concentrations of oligomeric and NpE AB in whole tissue homogenate and synaptosome fraction from DMN regions (Aim 1). We will also correlate these changes with neuropathology (e.g. tau) of the cholinergic basal forebrain neurons which project to these cortical areas and are studies in subprojects 1 and 3. In Aim 2, dendritic spine density will be quantified, by complementary analyses of a post-synaptic protein biochemical assay and confocal microscopy in tissue sections, and correlated with variables quantified in Aim 1. Aim 3 will quantify cholinergic, glutamatergic, and GABAergic terminals in DMN regions to determine how they change relative to increased oligomeric AB in synaptosomes, NpE AB, PiB binding, and to changes in dendritic spines in HP-NCl, MCI, and AD. Elucidation ofthe histopathological and biochemical signatures of clinical transitions from preclinical to MCI to AD will guide development of novel diagnostic imaging and therapic agents.